The research supported by grant R01 DK41526 for the past 23 years provided findings which allowed us to propose a new model of diabetic nephropathy that is centered on progressive renal decline, not on abnormalities in albuminuria. We found that onset and early progression of renal decline that leads to ESRD are strongly associated with high plasma levels of TNF receptors 1 & 2 (TNFR1, TNFR2). Mechanisms that account for these associations are unknown. To study them we conducted a preliminary study in 110 T1D patients with CKD stage 3. Using the SOMAscan platform which measures levels of 1128 proteins, we identified 31 proteins in baseline plasma that were extremely good, highly statistically significant predictors of ESRD development during 10-year follow-up. The remarkable finding of our study was that the significant proteins included multiple ligands (n=7) and receptors (n=9) of the TNF superfamily that, except for TNFR1 and TNFR2, have never been implicated in kidney diseases. Considering these new findings, we postulate that many ligands and receptors of the TNF superfamily (or a subset) that contribute to progression to ESRD are also involved in both the onset and progression of early renal decline in diabetes. The proposed research uses a custom-made SOMAscan platform of 35 TNF superfamily members) with 20 additional proteins to measure concentration of these candidate proteins in plasma specimens obtained at baseline and during follow-up of T1D and T2D cohorts. Relating concentrations of candidate proteins at baseline and during follow-up with risk of renal decline or ESRD will allow us to determine which ligands and receptors are initiators/drivers of the disease process and which change as a consequence of progressive renal decline. The proposed research has the following specific aims. 1) To establish plasma profiles of ligands and receptors of the TNF superfamily that are associated with risk of late renal decline that leads to ESRD in T1D in the Joslin Proteinuria Cohort; 2) To establish plasma profiles of ligands and receptors of the TNF superfamily that are associated with risk of onset and progression of early renal decline in T1D in the 2nd Joslin Kidney Study; 3) To establish plasma profiles of ligands and receptors of the TNF superfamily that are associated with the risk of onset and progression of early renal decline in T2D Pima Indians. This will test the generalizability of the findings obtained in T1D; 4) To determine the relationship between the revealed plasma profiles of ligands and receptors of the TNF superfamily and morphological lesions in kidney biopsies from T2D Pima Indians; 5) To determine the relationship between the revealed plasma profiles of ligands and receptors of the TNF superfamily and transcript patterns in kidney biopsies from T2D Pima Indians. The proposed research will test many novel hypotheses and has a very high probability of generating findings that will accelerate etiological studies of diabetic nephropathy Its success is assured as follow-up data and a biobank of specimens from all members of the Joslin Cohorts and Pima Indian Cohort are currently in hand.